Table S1 – S4. Details of published studies with low/intermediate/high risk surgery of in-hospital/ 30-day mortality after cardiac surgery
(1990-2012).
Table S1. Details of published studies with low risk surgery of in-hospital/ 30-day mortality after cardiac surgery (1990-2012).
Study
Study design
Bernet 1999[1]
RCT single-center,
double-blind,
Switzerland
Blauhut
1994[2]
RCT single-center,
Austria
Casati 1999[3]
RCT single-center,
unblinded, Italy
Casati 2000[4]
RCT single-center,
unblinded, Italy
Jun 1996-Jul 1997
Dietrich
2008[5]
RCT single-center,
double-blinded,
Germany
Diprose
2005[6]
RCT single-center,
double-blinded,
United Kingdom
Sample size/
Intervention
70 cases
N= 28 aprotinin
N=28 tranexamic
acid
45 cases
N=14 aprotinin
N=14 tranexamic
acid
N=14 control
210 cases
N=67 aprotinin
N=70 tranexamic
acid
N=66 ε-aminocaproic
acid
1,040 cases
N=518 aprotinin
N=522 tranexamic
acid
220 cases
N=110 aprotinin
N=110 tranexamic
acid
186 cases
N=60 aprotinin
N=60 tranexamic
Inclusion criteria/
Type of surgery
Isolated CABG
Exclusion criteria
(cardiac related)
Unstable angina
Isolated CABG
Isolated CABG
Isolated CABG
(~75%),
single valve surgery
(~25%)
Isolated CABG
(~60%),
single aortic valve
surgery (~40%)
Isolated CABG
(~75%),
single valve surgery
Analysis method
Mortality
Risk
Quality
Chi-square
or Fisher exact test
No
specified
Low
18
Redo operation,
therapy with
antiplatelets, heparin
or oral anticoagulants,
emergency surgery
EF< 35%, need of
ventricular assist
device for weaning
from CPB
Not specified
In-hospital
Low
18
Chi-square
or Fisher exact test
In-hospital
Low
17
Not specified
Chi-square
or Fisher exact test
In-hospital
Low
17
Redo operation,
previous exposure to
aprotinin, emergency
operation
Redo operation.
combined surgery,
two or more
Chi-square
or Fisher exact test
In-hospital
Low
20
Chi-square
or Fisher exact test
In-hospital
Low
19
1
Study
Study design
Greilich
2009[7]
RCT single-center,
double-blinded, US
Sep 1998-Jan 2001
Hekmat
2004[8]
RCT single-center,
double-blinded,
Germany
Kuitunen
2005[9]
RCT single-center,
double-blinded,
Finland
Landymore
1997[10]
RCT single-center,
double-blinded,
Canada
Misfeld
1998[11]
RCT single-center,
double-blinded,
Germany
Mongan
1998[12]
RCT single-center,
double-blinded, US
Lindvall
2008[13]
Retrospective
analysis of matched
Sample size/
Intervention
acid
N=60 control
81 cases
N=26 aprotinin
N=25 ε-aminocaproic
acid
N=27 control
120 cases
N=60 aprotinin
N=58 tranexamic
acid
60 cases
N=20 aprotinin
N=20 tranexamic
acid
N=20 control
184 cases
N=48 aprotinin
N=56 tranexamic
acid
N=44 ε-aminocaproic
acid
N=50 control
42 cases
N=14 aprotinin
N=14 tranexamic
acid
N=14 control
180 cases
N=75 aprotinin
N=75 tranexamic
acid
N=30 control
2,018 cases
Inclusion criteria/
Type of surgery
(~25%)
Isolated CABG
Exclusion criteria
(cardiac related)
antiplatelet therapies,
emergency operation
Emergency operation,
LVEF<30%
Analysis method
Mortality
Risk
Quality
Chi-square
or Fisher exact test
30-day
Low
19
Isolated CABG
Redo operation,
Combined surgery,
LVEF<40%
Fisher exact test
In-hospital
Low
18
Isolated CABG
Pre-operative
anticoagulants or
antiplatelet drug
Not specified
In-hospital
Low
17
Isolated CABG
(at least 3 bypass
grafts)
Redo operation,
Antiplatelet therapy
Chi-square test
In-hospital
Low
12
Isolated CABG
Not specified
Not specified
In-hospital
Low
14
Isolated CABG
Coagulopathy
Chi-square test
In-hospital
Low
17
Isolated CABG
Pre-operative
clopidogrel in centre
Fisher’s exact test,
30-day
Low
16
2
Study
Study design
cohort from 2 centres
in Sweden (one
centre used aprotinin
and the other
tranexamic acid)
2001 – 2003
Karkouti
2010[14]
Sander
2010[15]
Stamou
2009[16]
Retrospective
analysis of
consecutive series,
single centre, Canada
Jan 2000 – May 2008
Sample size/
Intervention
Matched paired
analysis (matched
according to age, sex,
and presence of acute
coronary syndrome)
N=200 aprotinin
N=200 tranexamic
acid
15,534 cases
15,365 analysed
Inclusion criteria/
Type of surgery
All types of cardiac
surgery with CPB
Propensity matched
pairs
(5:1 ratio)
Low/high risk:
N=579/ 193 aprotinin
N=577/ 195
tranexamic acid
Retrospective
analysis of
consecutive series,
single centre,
Germany
Jan 2006 – Dec 2006
900 cases
Retrospective
analysis of
consecutive series,
single centre, US
Jan 2002 - Dec 2006
2,101cases
All types of cardiac
surgery with CPB
Exclusion criteria
(cardiac related)
using aprotinin
Analysis method
Mortality
Patients who did not
receive aprotinin or
tranexamic acid and
those who participated
in the BART trial
Multivariable
logistic regression
Not specified
Multivariable
logistic regression
Propensity matched
pairs
(5:1 ratio)
N=570 aprotinin
N=114 ε-
Off-pump CABG, coadministration of both
aprotinin and εaminocaproic acid
Quality
Differences
between survival
curves were
analysed by using
the log-rank test
In-hospital
Propensity score
adjustment
In-hospital
Low/ high risk:
N=342/ 215 aprotinin
N=231/ 105
tranexamic acid
Isolated CABG
(~75-80%), single
valve surgery
(~15%), combined
surgery (~3-8%)
Risk
Multivariable
logistic regression
In-hospital
and 30-day
Subgroup
1: Low
Subgroup
2:
High
(predicted
risk for
major
adverse
events >
0.3
Subgroup
1: Low
Subgroup
2:
High (open
heart
surgery)
Low
19
21
20
Propensity score
adjustment
(using proportional
hazard Cox model)
3
Study
Kristeller
2007[17]
Martin
2008[18]
Shaw 2008[19]
Study design
Retrospective
analysis of
consecutive series,
single centre, US
Nov 2003 - Dec 2005
Sample size/
Intervention
aminocaproic acid
742 cases
335 analysed
N=162 Aprotinin
N= 173 εaminocaproic acid
Retrospective
analysis of
consecutive series,
single centre,
Germany
Sep 2005 - Jun 2006
1,239 cases
1,188 analysed
Retrospective
analysis of
consecutive series,
single centre, US
Jan1996 -Dec 2005
10,275 cases
Low/ high risk:
N=430/ 166 aprotinin
N=415/ 177
tranexamic acid
N=1,343 aprotinin
N=6,776 εaminocaproic acid
N=2,029 control
Inclusion criteria/
Type of surgery
Exclusion criteria
(cardiac related)
Low risk of
bleeding:
Isolated CABG ±
another surgical
procedure (ligation
of the left atrial
appendage, transmyocardial laser
revascularization,
and atrial fibrillation
ablation)
Low risk: isolated
CABG, single valve
surgery
High risk of bleeding:
Redo operation,
valve surgery,
aortic surgery,
urgent or emergent
operations,
use of clopidogrel or
warfarin
Chi-square test
In-hospital
Low
15
No antifibrinolytic
therapy, multiple
drugs, or dose of the
antifibrinolytic drug
was not sufficient
Chi-square test
30-day
Subgroup
1: Low
18
Not specified
Multivariable
logistic regression
High risk: operations
for bleeding, e.g.,
combined and redo
operations, aortic
surgery
Isolated CABG
(~85%),
CABG+valve
surgery (~10%)
Analysis method
Mortality
Kaplan-Meier
analysis and
Mantel–Cox logrank test
Risk
Quality
Subgroup
2:
High
30-day
Low
22
Propensity score
adjustment
Kaplan–Meier
comparison and
Cox proportionalhazards survival
analysis
Key characteristics of studies including design, type of surgery, sample size, inclusion/exclusion criteria, analysis method, and measured outcomes. CABG, coronary artery
bypass grafting; RCT, randomized controlled trial. Quality assessment of included studies with the Downs and Black score [total score from 0 (poor) to 29 (excellent)].
4
Table S2. Details of published studies with intermediate risk surgery of in-hospital/ 30-day mortality after cardiac surgery (1990-2012).
Study
Study design
Later 2009[20]
RCT single-center,
double-blinded,
The Netherlands
Jun 2004- Oct 2006
DeSantis
2011[21]
Retrospective
analysis of
consecutive series,
single centre, US
Oct 2005 – Oct 2008
Schneeweiss
2008[22]
Retrospective
analysis of
prospective database
of hospital
administration data
used for hospital
reimbursement (US)
Sample size/
Intervention
333 cases
N=96 aprotinin
N=99 tranexamic
acid
N=103 control
781 cases
N=325 aprotinin
N=206 tranexamic
acid
N=250 εaminocaproic acid
162,700 cases
78,199 analysed
Propensity matched
pairs (1:1 ratio)
N=4,799 aprotinin
N=4,799 εaminocaproic acid
Apr 2003 – Mar 2006
Mangano
2006[23]
Retrospective
analysis of
consecutive series,
69 institutions in
North and South
America, Europe, the
Middle East, and
Asia
5,436 cases
4,374 analysed
N=1,295 aprotinin
N=822 tranexamic
acid
N=883 εaminocaproic acid
N=1,374 control
Inclusion criteria/
Type of surgery
Isolated CABG
(~30%),
single valve surgery
(~30%), combined
surgery (~40%)
CABG ± valve
surgery (40-60%),
single valve surgery
(30-40%), heart
transplantation (717%)
Exclusion criteria
(cardiac related)
Redo operation,
antiplatelet therapy,
emergency
operation
Analysis
method
Chi-square test
Congenital surgery
,
LVAD implantation
Multivariable
logistic
regression
Isolated CABG
(~40%),
Complex CABG
surgery (~60%) was
defined as
emergency
admission, repeat
CABG, or additional
cardiac surgery on
the day of CABG
Isolated CABG
(primary surgery;
70%), combined
surgery (complex
surgery; 30%)
Did not receive
antifibrinolytic
agent, multiple
antifibrinolytic
agents, received
tranexamic acid
Multivariable
logistic
regression
Multiple
antifibrinolytic
agents, inadequate
dose of
antifibrinolytic
agent
Multivariable
logistic
regression
Mortality
Risk
Quality
Inhospital
Interme
diate
22
Inhospital
Interme
diate
21
Inhospital
Interme
diate
20
Inhospital
Interme
diate
20
Propensity score
adjustment
Propensity
matched pairs
Statistics for
direct
comparison
aprotinin vs.
active
5
Study
Wagener
2008[24]
Waldow
2009[25]
Maslow
2008[26]
Study design
Sample size/
Intervention
Prospective analysis
of consecutive series,
single centre, US
Jul 2004-Jan 2006
428 cases
369 analysed
Prospective analysis
of consecutive series,
single centre,
Germany
Sep 2006-Mar 2007
708 cases
Retrospective
analysis of
consecutive series,
single centre, US
2000-2007
144 cases
123 analysed
N=205 aprotinin
N=164 εaminocaproic acid
N=369 aprotinin
N=339 tranexamic
acid
N=41 aprotinin
N=82 ε-aminocaproic
acid
Inclusion criteria/
Type of surgery
Isolated CABG
(~20%), single valve
surgery (~30-50%),
combined surgery
(~20%), redo
operation, multiple
valve surgery
Isolated CABG
(~35%), isolated
valve surgery
(~30%),
CABG+valve
surgery (~15%),
CABG±valve±aortic
surgery (~10%), and
others
Isolated CABG
(~60-75%),
isolated valve
surgery (~10-15%),
CABG+valve
(~10%), redo
operation (~2-10%)
Exclusion criteria
(cardiac related)
Off-pump surgery
Analysis
method
(tranexamic acid/
ε-aminocaproic
acid) were not
calculated
Not specified
Mortality
Risk
Quality
Inhospital
Interme
diate
19
Redo operation,
emergency
procedures, preoperative
instability,
transplantation
Kaplan-Meyer
survival
30-day
Interme
diate
17
Emergency surgery,
pre-operative
instability, use of
hypothermic
cardiac arrest
Fisher‘s exact
test
Inhospital
Interme
diate
17
Key characteristics of studies including design, type of surgery, sample size, inclusion/exclusion criteria, analysis method, and measured outcomes. CABG, coronary artery
bypass grafting; RCT, randomized controlled trial. Quality assessment of included studies with the Downs and Black score [total score from 0 (poor) to 29 (excellent)].
6
Table S3. Details of published studies with high risk surgery of in-hospital/ 30-day mortality after cardiac surgery (1990-2012).
Study
Study design
Fergusson
2008[27]
RCT, multi-center,
double-blind,
19 Canadian centres
Aug 2002-Oct 2007
Nuttall
2000[28]
Wong 2000[29]
Jakobsen
2009[30]
Sniecinski
2010[31]
RCT, single-center,
double-blinded, US
RCT, single-center,
double-blinded,
Canada
Retrospective
analysis of
consecutive series,
single centre,
Denmark
Jan 2003 – Dec 2006
Retrospective
analysis of
consecutive series,
Sample size/
Intervention
2,331 cases
N=781 aprotinin
N=770 tranexamic
acid
N=780 εaminocaproic acid
168 cases
N=40 aprotinin
N=45 tranexamic
acid
N=32 tranexamic
acid+ autologous
blood collection
N= 43 control
80 cases
N=39 aprotinin
N=38 tranexamic
acid
3,586 cases
3,535 analysed
Propensity matched
pairs (1:1 ratio)
N= 534 aprotinin
N= 534 tranexamic
acid
160 cases
N=82 aprotinin
Inclusion criteria/
Type of surgery
Redo operation
(~10%),
CABG+other
procedure (~55%),
multiple valve
surgery, surgery of
the ascending aorta
or aortic arch
Redo operation
(CABG, combined
surgery)
Exclusion criteria
(cardiac related)
Isolated CABG,
isolated valve surgery,
congenital heart
surgery, heart
transplant, LVAD
implantation
Analysis method
Mortality
Risk
Quality
Multivariable
logistic regression
30-day
High
27
history of
thrombolytic,
warfarin, or heparin
therapy, Congenital
heart disease
Not specified
Not
specified
High
24
Redo operation,
multiple valve
surgery, combined
procedures, or aortic
arch operation
Antifibrinolytic or
thrombolytic, or
anticoagulant therapy
Not specified
In-hospital
High
22
Redo operation,
multiple cardiac
procedures, aortic
surgery, high comorbidity and
membership in
Jehovah’s Witnesses
Invalid personal
identifier, multiple
procedures during
study period
Multivariable
logistic regression
30-day
High
20
Redo operation,
cardiac surgery
requiring deep
Not specified
Fisher‘s exact test
In-hospital
High
14
Propensity score
adjustment
7
single centre, Japan
Jan 2006 - Nov 2008
N=78 tranexamic
acid
hypothermic
circulatory arrest
(aortic surgery
(ascending,
descending, and/or
arch) ± CABG ±
valve procedures)
Key characteristics of studies including design, type of surgery, sample size, inclusion/exclusion criteria, analysis method, and measured outcomes. CABG, coronary artery
bypass grafting; RCT, randomized controlled trial. Quality assessment of included studies with the Downs and Black score [total score from 0 (poor) to 29 (excellent)].
8
Table S4. Factors included in the regression analyses
Study
Lindvall
2008
Karkouti
2010
Propensity score analysis
Age, sex, and presence of acute coronary syndrome
Preoperative patient characteristics (demographics
(age, sex, body surface area), important
comorbidities (hypertension, diabetes mellitus,
peripheral vascular disease, cerebrovascular disease,
atrial fibrillation, left ventricular ejection fraction,
recent myocardial infarction, recent cardiac,
catheterization, active endocarditis), preoperative
creatinine, hemoglobin, platelet, and international
normalised ratio of pro- thrombin time), surgeryrelated variables (surgeon, procedure, urgency, and
cardio-pumonary bypass duration), and patients’
large-volume red blood cell transfusion risk score
Sander 2010
Stamou
2009
Shaw 2008
Gender, NYHA class, previous coronary artery
bypass graft surgery, congestive heart failure Status,
age, surgeon, type of surgery
Age, race, angina, aortic regurg grade, cardiopulmonary bypass used, cardio-pulmonary bypass
duration, pre-operative creatinine, previous cerebro
vascular accident, family history, hypertension,
hypercholesterolemia, side of internal mammary
used, pre-operative inotropes, pre-operative
nitroglycerin, ace inhibitors, anti-platelet therapy,
diuretics, mitral valve procedure, tricuspid valve
procedure, valve surgery, aortic valve stenosis,
number distal anastomosis, other cardiac surgery,
parsonnet score, previous cardiovascular
intervention, pre-operative cardiac arrest, preoperative renal dysfunction, pre-operative
salicylates, smoking history, operative urgency)
DeSantis
2011
Schneeweiss
2008
41 covariates and 10 markers of coexisting
conditions and disease severity, no further detail
given
Mangano
2006
Propensity score using 45 treatment- selection
covariates
Mortality analysis
Prior myocardial infarction and ejection
fraction
Cubic spline function curves of the
observed rates of mortality were plotted
against the predicted risk for major adverse
events (as calculated by the Toronto Risk
Score regression formula)
Age, cardio-pulmonary bypass time,
EuroSCORE, type of surgery, creatinine,
hemoglobin, and type of antifibrinolytic
Diabetes, chronic renal insufficiency,
congestive heart failure, unstable angina,
Age, cardio-pulmonary bypass time
EuroSCORE, age, year, valve surgery,
propensity score decile
EuroSCORE, cardio-pulmonary bypass
time, surgery type (ie, valve
replacement/repair versus coronary artery
bypass graft surgery alone), presence or
absence of diabetes, and the preoperative
use of angiotensin-converting-enzyme
inhibition, diuretics, or aspirin
Age, gender, race, past or current smoker,
year, emergency admission, day of
operation, marital status, redo, additional
cardiac surgery, complex surgery, extent of
disease, previous percutaneous coronary
intervention, diabetes, hypertension, liver
disease, cancer, COPD/Asthma, previous
myocardial infarction, previous stroke,
endocarditis, renal disease, peripheral artery
disease, hospital size, number of coronary
artery bypass graft procedures performed,
region, hospital location
97 covariates considered, no further detail
given
9
Jacobsen
2009
Fergusson
2008
Female, age, chronic pulmonary disease , extra
cardiac arteriopathy, neurologic dysfunction disease,
previous cardiac surgery, preoperative serum
creatinine >200 mmol/l, active endocarditis, critical
perioperative state, unstable angina, left ventricular
function, recent myocardial infarct, pulmonary
hypertension, emergency surgery, coronary artery
bypass graft surgery surgery, single procedure,
multiple procedures, surgery on thoracic aorta, single
valve surgery, post-infarct septal rupture,
EuroSCORE, diabetes mellitus, Charlson comorbidity index, year of surgery
Operative procedure, age, sex, presence of
coexisting illnesses, preoperative use of
aspirin, and the ASA risk score
10
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12
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